Abstract
Purpose :
Genetic testing for RPE65 retinopathies is critical to providing access to potentially sight preserving gene therapy to qualifying patients. Limiting the number of variants of uncertain significance (VUS) and increasing the number of accurately curated variants in public databases is vitally important to ensure that all patients who could potentially benefit from this clinical therapy are appropriately identified.
Methods :
In 2015, the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) developed a framework to assess variant pathogenicity; however, the guidelines were written broadly. The Clinical Genome Resource (ClinGen), funded by the National Human Genome Research Institute, convened the Leber Congenital Amaurosis (LCA)/Early-onset Retinal Dystrophy Variant Curation Expert Panel (LCA VCEP) in July 2020 to develop rule specifications for curating variants in the REP65 gene through their Federatal Drug Administration approved process.
The LCA VCEP members meet monthly to specify ACMG-AMP rules, initially for the RPE65 gene, and to discuss resulting variant assertions. There are plans to expand this work to additional genes starting with GUCY2D, AIPL1 and CEP290 once rule specifications for the RPE65 gene are completed. Each rule was assessed for its appropriateness for the RPE65 gene and whether there would be any benefit to adding detailed criteria for its use and/or modifying its strength based on availability of evidence.
Results :
Variant curation specifications were applied to 19 ACMG-AMP rule criteria and 9 rules were deemed not applicable to the RPE65 gene. Criteria modifications included setting allele frequencies in normal controls, defining phenotype criteria and conditions for adjusting rule strength. Fifty RPE65 variants were chosen for a pilot study to test the rule specifications, comprising of 20 pathogenic/likely pathogenic, 15 VUS and 15 benign/likely benign variants.
Conclusions :
Results of this effort will aid clinical variant interpretation of the RPE65 gene and help standardize variant curations across laboratories. Expert level variant curation from this VCEP will be deposited in the ClinVar database for public access.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.